TAILIEUCHUNG - Báo cáo khoa học: Quantitative assessment of the glyoxalase pathway in Leishmania infantum as a therapeutic target by modelling and computer simulation

The glyoxalase pathway ofLeishmania infantumwas kinetically character-ized as a trypanothione-dependent system. Using time course analysis based on parameter fitting with a genetic algorithm, kinetic parameters were estimated for both enzymes, with trypanothione derived substrates. A Kmof mmand aVof )1 Æmg )1 for glyoxalase I, and a Kmof mmand aVof )1 Æmg )1 for glyoxalase II, were obtained. | iFEBS Journal Quantitative assessment of the glyoxalase pathway in Leishmania infantum as a therapeutic target by modelling and computer simulation Marta Sousa Silva1 Antonio E. N. Ferreira1 Ana Maria Tomas2 3 Carlos Cordeiro1 and Ana Ponces Freire1 1 Centro de Quimica e Bioquimica Departmento de Quimica e Bioquimica Faculdade de Ciencias da Universidade de Lisboa Portugal 2 ICBAS - Instituto de Ciencias Biomedicas AbelSalazar Universidade do Porto Portugal 3 Instituto de Biologia Molecular e Celular Universidade do Porto Portugal Keywords Leishmania trypanothione methylglyoxal glyoxalase modelling Correspondence C. Cordeiro Centro de Quimica e Bioquimica Departmento de Quimica e Bioquimica Faculdade de Ciencias da Universidade de Lisboa Edificio C8 Lisboa Portugal Fax 351 217500088 Tel 351 217500929 E-mail caac@ http enzimol Note The mathematical model described here has been submitted to the Online Cellular Systems Modelling Database and can be accessed free of charge at http . database silva Received 12 November 2004 revised 21 January 2005 accepted 28 February 2005 doi The glyoxalase pathway of Leishmania infantum was kinetically characterized as a trypanothione-dependent system. Using time course analysis based on parameter fitting with a genetic algorithm kinetic parameters were estimated for both enzymes with trypanothione derived substrates. A Km of mM and a V of imol-min_1-mg_1 for glyoxalase I and a Km of mM and a V of imol-min_1-mg_1 for glyoxalase II were obtained. Modelling and computer simulation were used for evaluating the relevance of the glyoxalase pathway as a potential therapeutic target by revealing the importance of critical parameters of this pathway in Leishma-nia infantum. A sensitivity analysis of the pathway was performed using experimentally validated kinetic models and experimentally determined metabolite concentrations and .

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